Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

Sebastijan Hobor, Maise Al Bakir, Crispin T. Hiley, Marcin Skrzypski, Alexander M. Frankell, Bjorn Bakker, Thomas B. K. Watkins, Aleksandra Markovets, Jonathan R. Dry, Andrew P. Brown, Jasper Aart, Hilda Bos, Diana Spierings, Dahmane Oukrif, Marco Novelli, Turja Chakrabarti, Adam H. Rabinowitz, Laila Ait Hassou, Saskia Litière, D. Lucas Kerr, Lisa Tan, Gavin Kelly, David A. Moore, Matthew J. Renshaw, Subramanian Venkatesan, William Hill, Ariana Huebner, Carlos Martínez-Ruiz, James R. M. Black, Wei Wu, Mihaela Angelova, Nicholas McGranahan, Julian Downward, Juliann Chmielecki, Carl Barrett, Kevin Litchfield, Su Kit Chew, Collin M. Blakely, Elza C. Bruin, Floris Foijer, Karen H. Vousden, Trever G. Bivona, Robert E. Hynds, Nnennaya Kanu (), Simone Zaccaria (), Eva Grönroos () and Charles Swanton ()
Additional contact information
Sebastijan Hobor: The Francis Crick Institute
Maise Al Bakir: The Francis Crick Institute
Crispin T. Hiley: The Francis Crick Institute
Marcin Skrzypski: The Francis Crick Institute
Alexander M. Frankell: The Francis Crick Institute
Bjorn Bakker: The Francis Crick Institute
Thomas B. K. Watkins: The Francis Crick Institute
Aleksandra Markovets: AstraZeneca
Jonathan R. Dry: AstraZeneca
Andrew P. Brown: AstraZeneca
Jasper Aart: AstraZeneca
Hilda Bos: University Medical Center Groningen
Diana Spierings: University Medical Center Groningen
Dahmane Oukrif: University College London Medical School
Marco Novelli: University College London Medical School
Turja Chakrabarti: University of California
Adam H. Rabinowitz: EMBL Meyerhofstraße 1
Laila Ait Hassou: European Organization for Research and Treatment of Cancer
Saskia Litière: Bioinformatics & Biostatistics; Francis Crick Institute
D. Lucas Kerr: University of California
Lisa Tan: University of California
Gavin Kelly: Bioinformatics & Biostatistics; Francis Crick Institute
David A. Moore: University College London Cancer Institute
Matthew J. Renshaw: The Francis Crick Institute
Subramanian Venkatesan: The Francis Crick Institute
William Hill: The Francis Crick Institute
Ariana Huebner: The Francis Crick Institute
Carlos Martínez-Ruiz: University College London Cancer Institute
James R. M. Black: University College London Cancer Institute
Wei Wu: University of California
Mihaela Angelova: The Francis Crick Institute
Nicholas McGranahan: University College London Cancer Institute
Julian Downward: The Francis Crick Institute
Juliann Chmielecki: AstraZeneca
Carl Barrett: AstraZeneca
Kevin Litchfield: The Francis Crick Institute
Su Kit Chew: The Francis Crick Institute
Collin M. Blakely: University of California
Elza C. Bruin: AstraZeneca
Floris Foijer: University Medical Center Groningen
Karen H. Vousden: The Francis Crick Institute
Trever G. Bivona: University of California
Robert E. Hynds: The Francis Crick Institute
Nnennaya Kanu: University College London Cancer Institute
Simone Zaccaria: University College London Cancer Institute
Eva Grönroos: The Francis Crick Institute
Charles Swanton: The Francis Crick Institute

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Date: 2024
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DOI: 10.1038/s41467-024-47606-9

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